Anti-excitatory compositions



ANTll-EXCIITATORY OMPOSHTIONS Hoseph Seifter, Philadelphia, Anthony L. Monaco, Norristown, and Franklin .ludson Hoover, Philadelphia, lPa., assignors to American Home Products Corporation, New York, N. Y., a corporation of Delaware No Drawing. Application November 17, 11955, $erial No. 547,528

3 Claims. (Cl. 1167-65) This invention relates to therapeutic-compositions and, more particularly, to compositions containing a phenothiazine derivative.

It has been found that oral and parenteral compositions may be prepared containing as an active ingredient a phenothiazine compound in the form of a water-soluble salt, the base having the following formula:

III R1 GHTCHTCHFN wherein R1 and R2 are intended to represent the lower alkyl radicals methyl and ethyl or, when combined with N in a ring structure, pyrrolidine and piperidine. The bases and their salts may be made by procedures known to the art, as, for example, disclosed in the patent to Charpentier, Patent No. 2,530,451, dated November 21, 1950.

The compositions of the invention have been found useful in excitatory conditions based on hypothalamic discharge, as muscle relaxants, and in the relief from mental tension. Specifically, the compositions have been found to be highly effective for the treatment of alcoholics and agitated psychotics. It may be noted that compositions containing compounds disclosed in the above-mentioned Charpentier patent do not have these therapeutic actions.

The compositions of the invention, in contrast to compositions containing halogenated phenothiazine derivatives, as, for example, chlorpromazine, are relatively and substantially less toxic and longer acting. The compositions also possess less liver injury potential and less deleterious effect on the hemopoietic system. Additionally, while chlorpromazine in parenteral form is extremely painful when used in the absence of a local anesthetic, and causes local inflammation, the compositions of the invention do not cause inflammation and require no local anesthetic, causing no noticeable pain or discomfort, whether used intramuscularly or intravenously.

The phenothiazine base may be prepared by reacting phenothiazine with an acid binding agent such as sodamide, lithium amide, sodium hydride, butyl lithium or metallic sodium in the presence of toluene or xylene. The reaction is carried out at the refluxing temperature of the solvent. The reaction product is then heated with trimethylene dihalide which may be a chlorobromide, dichloride or dibromide, with the former preferred since better yields are obtained and a relatively lower reaction temperature is needed. The IO-(y-halo-n-propyl)-phenothiazine thus formed is then reacted with the appropriate di-lower alkylamine in the presence of a solvent such as butyl or amyl alcohol at a temperature in the range of about 115 to 140 C. The desired product is formed as the hydro-halide salt.

Useful salts of the phenothiazine base are salts which moans Patented July 16, i957 are non-toxic at the therapeutic dosage level and, where the salts are to be used in a dry composition, non-hygroscopic. A preferred salt, meeting the latter characteristic as well as being non-toxic, is the hydrochloride. Other salts may of course be used depending on the particular type of composition contemplated. The following salts of 10-('y-dimethylaminopropyl)phenothiazine have been prepared:

For oral preparations, capsules or tablets are made up containing not less than 10 mg. of active therapeutic ingredient. Because the active ingredient is relatively nontoxic, capsules or tablets may be prepared to contain as high as 200 mg. of the phenothiazine derivative. Preferably, suitable compositions contain from about to 100 mg. of active ingredient. Besides the active ingredient, the tablet may contain the usual excipients or diluents as well as a disintegrating agent.

In preparing a tablet, it is first necessary to make up a base granulation containing powdered sucrose, powdered lactose, powdered corn starch, powdered calcium sulfate (dihydrated) or combinations of such substances. If de sired, a color may be incorporated at the same time by dissolving it in a portion of the granulating solution or as a dry impalpable powder before moistening with gelatin, acacia, etc. i

The uniformly dampened material is then screened coarsely (No. 4 to No-12 mesh, depending on the properties of the dampened mass), spread on trays in thin layers, and dried at approximately to C. When dry, the mass is further sieved through a No. 16 or No. 20 mesh screen.

The phenothiazine derivative, in the form of a uniformly fine powder, is then mixed with a lubricating agent, such as calcium or magnesium stearate, and a disintegrating agent as, for example, powdered corn starch redried. After the mixture has been completed, it is then added to the base granulation, as previously described, and the mixed material is then compressed in tablet form.

A typical formulation for tablets may be as follows:

15 mg. 10-(' -methylethylamino-n-propyl)-phenothiazine hydrochloride,

3.5 grains granulated calcium sulfate, dehydrated,

' grain magnesium stearate, and

grain powd. corn starch, redried.

Concerning compositions intended for parenteral use, these may be made up either in lyophilized or dried form for reconstitution with water to make up the desired solution or as an aqueous solution for immediate use. The phenothiazine salt has been found to be easily destroyed by both light and heat and, to protect the active ingredient, it is necessary to use stabilizing agents. The most useful stabilizing agent has been found to be sodium formaldehyde sulfoxylate. While ascorbic acid is also useful as a stabilizer, it is not as effective as the aforesaid sulfoxylate compound. The sulfoxylate may be used in an amount ranging from about .05 to about 0.5% by weight based on total composition with the optimum being in the neighborhood of about 0.2%.

In addition to the stabilizer, it is also necessary to provide a bulfering agent capable of maintaining a pH in the range of about 4.5 to not more than about 5.8. As buffering agents, sodium citrate with citric acid has been found superior to other well known buffering agents which may be used in the composition. The amount found most suitable for providing buffering action and stability is in the range from about 0.25 to 0.45% by weight based on the total composition.

In addition to the aforesaid ingredients, apreservative is also provided which may be selected from those well known in the art. A preferred preservative is Thimerosal which not only appears to be effective as an antibacterial agent but also provides some antioxidant or stabilizing action. The preservative is generally present in trace amounts ranging from about 0.005% to about 0.01% by weight.

Reverting to the stabilizing agent, namely, sodium formaldehyde sulfoxylate, the action of this material is somewhat enhanced when used together with thiourea. When using the latter substance in addition to the sulfoxylate compound, it may be present in the composition in approximately the same amounts as the preservative.

A typical formulation for a parenteral composition is as follows:

('y dimethylamino n propyl)-phenothiazine T he above formulation may be used either in lyophilized form or as an aqueous final product. In the formulation as given, one may decrease the amount of phenothiazine salt to as low as 10 mg. or increase the amount within the range previously given.

We claim:

1. A therapeutic composition in dosage form useful in excitatory and agitated conditions comprising a salt of phenothiazine derivative whose base has the formula Hr C Hr C Hr-N wherein R1 and R2 each represent a lower alkyl radical of the group consisting of methyl and ethyl which may be joined to form a member of the group consisting of pyrrolidine and piperidine, in an amount between about 10 to 200 mg., a stabilizing agent in an amount from about .05 to 0.2% and a buffering agent in an amount from about 0.25% to 0.45%.

3. The composition of claim 2, wherein the stabilizing agent comprises sodium formaldehyde sulfoxylate.

References Cited in the file of this patent UNITED STATES PATENTS Charpentier May 6, 1952 Cusic Aug. 24, 1954 QTHER REFERENCES Viaud: Les Amines Derivees de la Phenothiazine. Reprinted from the J our. of Pharm. and Pharmacology, 1954, 6, pp. 361-389. 

1. A THERAPEUTIC COMPOSITION IN DOSAGE FORM USEFUL IN EXCITATORY AND AGITATED CONDITIONS COMPRISING A SALT OF PHENOTHIAZLINE DERIVATIVE WHOSE BASE HAS THE FORMULA 